NBK Flashcards
What are the progenitors of NK cells?
→common lymphoid progenitor
→same as Tcells and Bcells
What do cytotoxic cells destroy?
→Cells infected with bacteria, viruses or parasites
→Tumour cells
What is CTL killing controlled by?
→T cell receptor recognition, with CD8 acting as a co-receptor
Compare the specificity of NK cells and CTLs
→CTL are highly specific
→NK cells have broad specificity
Why do we need more than one type of cytotoxic lymphocyte?
→To combat infection in the period before a T cell response develops
→To provide an alternative system when a tumour or infected cells evade Cytotoxic T cell responses
→To provide an additional mechanism for killing infected targets via antibody recognition
How long after first encounter do CTL kick in?
→7 days
What is the link between NK cells and cancer?
→Medium and high cytolytic function was associated with reduced cancer risk
Summarise intracellular proteins presentation on MHC1
→antigen processed in phagosome
→peptide transport into ER
→peptide binding by MHC1
→MHC1 presents peptide of cell surface
Describe the structure of MHC1
→2 alphas helices forming edges of groove.
→Beta sheets forming base of peptide binding groove
→B2 macroglobulin supports peptide binding groove
Compare alpha helices and beta2- microglobulin
alpha helices
→polymorphic
→glycosylated
→inserted in membrane
beta2-microglobulin
→not polymorphic
→not glycosylated
→not inserted in membrane
Which chromosome is the MHC gene found?
→chromosome 6
How many MHC1 and MHC2 proteins?
→3 MHC1(6 MHC1 genes because of two alleles)
→3 MHC2
What is the most genetically diverse genes?
→HLA
Where is the polymorphs found in MHC?
→in the upper peptide-binding part
Where is variation found in the MHC1 and MHC2 binding groove?
→MHC1 in the pocket of groove
MHC2 in the beta chain groove
What are pockets in the MHC groove formed from?
→amino acids
→creates different charges
How long is the peptide that binds into pockets?
→9 amino acids in length and they will bind to corresponding pockets
What two things do TCR recognise?
→MHC protein itself
→Antigenic peptide presented by MHC protein
In what two situations would someone have foreign MHC1?
→pregnancy
→transplant
How does TCR bind to MHC1?
→diagonal footprint that cuts across both alpha helices of MHC1 with the peptide in between
What is a co-receptor for MHC1?
→CD8
→CD8 binds to the support domains (a3 and b2m)
Which domains does TCR bind to on MHC1?
→a1a2 domains
How do pathogens subvert presentation by MHC-I?
→Inhibit MHC-I transcription (adenovirus)
→Block peptide transport into the endoplasmic reticulum (HSV)
→Retain MHC-I in endoplasmic reticulum (adenovirus, HCMV)
→Target MHC-I for disposal from the endoplasmic reticulum (HCMV)
→Downregulate MHC-I from cell surface (HIV)
What is the normal function of KIR in healthy cells?
→KIR recognise MHC-I they inhibit NK cells from releasing lytic granules
What does KIR cells do when there is no MHC?
→no KIR inhibition,
→lytic granules will be released to lyse the target
→missing self
Where does KIR bind on MHC1?
→to the same face of MHC-I as the T cell receptor
→binds just one end of the MHC but sees the top and bottom of grove and the antigen- sees a lot less than TCR
Compare the specificity of KIR and TCR?
→KIR has less specificity than TCR
→KIR can recognise subsets of MHC1
→KIR is also polymorphic
What other natural cytotoxicity receptors are found on NK cells and what do they bind to?
→NKp46 is known to bind viral hemagglutinin
→NKp44 – binds a ligand that is expressed on tumor cells and upregulated by viral infection
→Ligand for NKp30 is a stress induced
protein
What does target cell death depend on?
→depends on balance of activating and inhibitory signals
Why do NK cells kill tumour cells?
→downregulating the expression of MHC class I →tumour cells also induce stress signals that activate NK cells
Describe ADCC
→Antibody-dependent cell-mediated cytotoxicity
→At the point of budding, viral proteins are expressed and antibodies are bound
→NK cells express a receptor that recognizes the Fc portion of antibodies
→ receptor delivers a strong activating signal when it recognizes antibodies bound to a cell surface
→Results in lysis of the target cell
Describe the lysis mechanism of NK cells
→NK cells and T cells carry granules filled with cytotoxic proteins
→Release cytotoxic granules at site of contact with target cell
What are three proteins in granules for lysis?
→perforin
→granzymes
→granulysin
What is the function of perforin?
→aids in delivering granules into cytoplasm of target cells
What is the function of granzymes?
→serine proteases
→activates apoptosis once in cytoplasm
What is the function of granulysin?
→has antimicrobial actions
→can help induce apoptosis
Describe the immunological synapse
→T cell receptors and co-receptors cluster at the site of cell-cell contact
→Triggers reorganisation of cytoskeleton
→polarises the T cell to release effector molecules at the point of contact
Why is polarisation of TCRs and co-receptors important?
→to prevent killing of healthy nearby cells
How does CD8 trigger apoptosis of Fas/FasL interaction?
→Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway
Why is FasL apoptosis used?
→used to dispose of unwanted lymphocytes
What does loss of FAD result in?
→autoimmune lymphoproliferative syndrome (ALPS)
Compare NKs and CTLs
→CTLs use CD8 as a co-receptor for MHC class I
→NK do not use a co-receptor for MHC class I, do not express CD8
Describe the FasL/Fas apoptosis pathway
→trimeric Fas ligand binds and trimerizes Fas
→Clustering of Death Domain in Fas cytoplasmic domains allow Fas to recruit FADD via death domain
→Clustered death effector domains of FADD recruit procaspase 8 via similar DED in the pro-caspase
